Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Evidence is reviewed that 5-HT (5-hydroxytryptamine, serotonin) acting through the 5-HT3 receptor subtype can influence behaviour relevant to anxiety, schizophrenia and cognitive disorders, and that 5-HT3 receptor antagonists such as ondansetron (CAS 116002-70-1) can correct behavioural disturbance in the absence of effect on normal behaviour. The 5-HT3 receptor antagonists exert a breadth of action over a wide dose range in rodent and primate models to inhibit aversive behaviour in animal models of anxiety and certain symptoms of withdrawal from drugs of abuse, alcohol, nicotine, diazepam and cocaine, to antagonise increased locomotor activity caused by mesolimbic dopamine excess, and facilitate performance in cognitive tests. The studies reveal an important role for 5-HT3 receptors in the regulation of limbic-cortical functioning, and a critical role for 5-HT3 receptor antagonists to establish the role of 5-HT3 receptors in schizophrenia, anxiety, drug withdrawal phenomena and cognitive disturbance. Preliminary clinical trials indicate a positive effect of ondansetron in anxiety, schizophrenia, alcohol withdrawal and age associated memory impairment.
 ...
PMID:Serotonin and psychiatric disorders. A key to new therapeutic approaches. 158 95

Rac-ML-1035 (MDL 201,035: 4-amino-5-chloro-2-[2-(methylsulfinyl)ethoxy]-N-[2-(diethylamino)ethyl] benzamide hydrochloride) is a racemic gastroprokinetic with serotonergic (5-hydroxytryptamine, 5-HT) activity and a novel chiral sulfoxide substituent. Chromatographic and chemical methods have been developed to resolve the enantiomers of rac-ML-1035, and the absolute configuration of the (R)-enantiomer has been determined. We also report pharmacological characterization of rac-ML-1035 and its respective isomers. Radioligand binding to rat cortical membranes revealed that (R)-ML-1035 (MDL 201,226) and (S)-ML-1035 (MDL 201,227) had equivalent activity at the 5-HT3 receptor. However, in isolated tissue studies including field-stimulated guinea pig ileum, field-stimulated rat fundic strip, and nonstimulated guinea pig ileum, (S)-ML-1035 was equally potent yet had greater maximal activity than (R)-ML-1035 in eliciting or facilitating cholinergic contractions. Thus, enantiomers of rac-ML-1035 can be resolved, and the relative configuration of these isomers influences their pharmacological activity.
 ...
PMID:The resolution, isolation, and pharmacological characterization of the enantiomers of a benzamide containing a chiral sulfoxide. 158 86

Serotonin (5-hydroxytryptamine; 5-HT) is found in the enteric nervous system where it has been implicated in controlling gastrointestinal motor function. A number of receptor or recognition sites have been identified in the gut, but recently most attention has focused on the 5-HT3 and 5-HT4 receptors. The functional role of the 5-HT3 receptor remains incompletely understood, but it is probably involved in the modulation of colonic motility and visceral pain in the gut. A number of selective 5-HT3 antagonists have been developed including ondansetron, granisetron, tropisetron renzapride and zacopride. While the substituted benzamide prokinetics (for example, metoclopramide, cisapride) also block 5-HT3 receptors in high concentrations, their prokinetic action is believed to be on the basis of their agonist effects on the putative 5-HT4 receptor. Some 5-HT3 antagonists have 5-HT4 agonist activity (for example, renzapride, zacopride) and others do not (for example, ondansetron, granisetron), while tropisetron in high concentrations is a 5-HT4 antagonist. Based on the pharmacological data, it has been suggested that specific 5-HT antagonists and agonists may prove to be beneficial in a number of gastrointestinal disorders including the irritable bowel syndrome, functional dyspepsia, non-cardiac chest pain, gastrooesophageal reflux and refractory nausea. In this review, the rationale for the use of these compounds is discussed, and the available experimental evidence is summarized.
 ...
PMID:Review article: 5-hydroxytryptamine agonists and antagonists in the modulation of gastrointestinal motility and sensation: clinical implications. 160 46

1. We describe the effects of pretreatment with 5-hydroxytryptamine (5-HT) receptor agonists and antagonists on neurogenically-mediated plasma protein extravasation ([125I]-albumin) in rat dura mater and in extracranial tissues (temporalis muscle fascia, conjunctiva, eyelid and lip) induced by electrical stimulation of the right trigeminal ganglion. 2. Leakage of [125I]-bovine serum albumin from blood vessels in dura mater following high intensity stimulation (1.2 mA, 5 ms, 5 Hz for 5 min) was significantly reduced by the intravenous administration of drugs active at 5-HT receptors with some selectivity for the 5-HT1 receptor subtypes: 5-carboxamidotryptamine (5-CT) (threshold dose, 1 ng kg-1); 5-benzyloxytryptamine (5-BT) (10, 30 or 100 micrograms kg-1); 8-hydroxydipropylaminotetralin (8-OH-DPAT) (300 micrograms kg-1); and as previously reported, sumatriptan (100 micrograms kg-1), dihydroergotamine (DHE) (50 micrograms kg-1); ergotamine tartrate (100 micrograms kg-1) and chronically administered methysergide (1 mg kg-1). 3. The putative 5-HT receptor antagonist, metergoline 100 micrograms kg-1, inhibited partially the effect of sumatriptan in dura mater providing additional evidence for a 5-HT1 receptor subtype-mediated mechanism, although it was not effective against 5-CT (1 ng kg-1). Methiothepin (300 micrograms kg-1) did not affect the response to sumatriptan. When administered at high concentrations (1 mg kg-1) methiothepin and metergoline decreased plasma protein extravasation in rat dura mater. 4. Pretreatment with the 5-HT2 receptor antagonists pizotifen, 300pugkg 1, or ketanserin, 300,ugkg ', or the 5-HT3 receptor antagonists MDL 72222, 300,ugkg-1, or ICS 205-930, 300pgkg-1, did not affect plasma protein leakage following electrical trigeminal stimulation. Blockade by sumatriptan of plasma protein extravasation was not inhibited by pizotifen (300,ug kg-1) or MDL 72222 (300pg kg- '). 5. The 5-HT receptor(s) mediating this response were present only on intracranial tissues innervated by the trigeminal nerve; plasma protein extravasation in extracranial tissues was not blocked by pretreatment with the equivalent or higher concentrations of the above drugs following low intensity trigeminal stimulation (0.1 mA, 5 ms, 5 Hz). 6. The putative 5-HT receptor(s) mediating this response were not present on sympathetic fibres innervating dura mater since unilateral removal of the superior cervical ganglion did not prevent the development of plasma protein extravasation nor did it affect the blockade by sumatriptan IOOpug kg- '. 7. The above pharmacological data suggest that intracranial vessels possess 5-HT receptor(s) which are coupled to inhibition of neurogenically-mediated plasma protein extravasation. These receptors cannot be detected on extracranial cephalic blood vessels innervated by the trigeminal nerve, although available evidence strongly suggests that the 5-HT receptors reside on perivascular trigeminal nerve fibres. The rank order of effective doses (threshold concentrations; 5-CT < 5-BT < DHE < sumatriptan < 8-OHDPAT) is most consistent with a 5-HTlB- or 5-HTlD-mediated response, among the known 5-HT1 family of receptors. However, the lack of effect of methiothepin against the actions of sumatriptan, or metergoline against the effects of 5-CT suggest important differences and the possibility that a previously unrecognized 5-HT receptor(s) is involved in this response.
 ...
PMID:Further characterization of the putative 5-HT receptor which mediates blockade of neurogenic plasma extravasation in rat dura mater. 165 72

In rats lightly restrained in horizontal cylinders, (+/-)-3,4-methylenedioxymethamphetamine (MDMA) dose dependently (0.16-10.0 mg/kg, s.c.) elicited spontaneous tail-flicks; that is, tail-flicks in the absence of extraneous stimulation. In contrast, amphetamine over a similar dose-range was inactive. Selective inhibitors of 5-hydroxytryptamine (5-HT) uptake and carrier-mediated 5-HT release, paroxetine and citalopram, did not induce spontaneous tail-flicks themselves and blocked those induced by MDMA. In distinction, maprotiline and bupropion, selective inhibitors of noradrenaline and dopamine uptake, respectively, failed to modify the action of MDMA. Spontaneous tail-flicks elicited by MDMA were unaffected by the selective 5-HT3 receptor antagonists, ICS 205,930 and GR 38032F. They were attenuated by the mixed 5-HT1/5-HT2 receptor antagonist, methiotepin, the mixed 5-HT1A/5-HT1B receptor antagonist, (-)-alprenolol and the mixed 5-HT1A/5-HT2 receptor antagonist, spiperone, but not by the selective 5-HT1C/5-HT2 receptor antagonists, ritanserin, ICI 169,369 and ketanserin. The novel 5-HT1A receptor antagonists, BMY 7378 and NAN-190, each abolished MDMA-evoked spontaneous tail-flicks. Selective D1, D2, alpha 1, alpha 2, beta 1 and beta 2 antagonists had little influence upon induction of spontaneous tail-flicks by MDMA. These data indicate that MDMA evokes spontaneous tail-flicks in the rat via a release of 5-HT which acts at 5-HT1A receptors. Thus, 5-HT1A receptors appear to be involved in the acute functional actions of MDMA.
 ...
PMID:Methylenedioxymethamphetamine induces spontaneous tail-flicks in the rat via 5-HT1A receptors. 167 9

In vivo and in vitro methods were used to characterize AHR-16303B, a novel compound with antagonistic action at 5-HT2 receptors and voltage-sensitive calcium channels. The 5-HT2 receptor-antagonistic properties of AHR-16303B were demonstrated by inhibition of (a) [3H]ketanserin binding to rat cerebral cortical membranes (IC50 = 165 nM); (b) 5-hydroxytryptamine (5-HT)-induced foot edema in rats (minimum effective dose, (MED) = 0.32 mg/kg orally, p.o.); (c) 5-HT-induced vasopressor responses in spontaneously hypertensive rats (SHR) (ID50 = 0.18 mg/kg intravenously (i.v.), 1.8 mg/kg p.o.), (d) 5-HT-induced antidiuresis in rats (MED = 1 mg/kg p.o.), and (e) platelet aggregation induced by 5-HT + ADP (IC50 = 1.5 mM). The calcium antagonist properties of AHR-16303B were demonstrated by inhibition of (a) [3H]nimodipine binding to voltage-sensitive calcium channels on rabbit skeletal muscle membranes (IC50 = 15 nM), (b) KCl-stimulated calcium flux into cultured PC12 cells (IC50 = 81 nM), and (c) CaCl2-induced contractions of rabbit thoracic aortic strips (pA2 = 8.84). AHR-16303B had little or no effect on binding of radioligands to dopamine2 (DA2) alpha 1, alpha 2, H1, 5-HT1 alpha, beta 2, muscarinic M1, or sigma opioid receptors; had no effect on 5-HT3 receptor-mediated vagal bradycardia; and had only minor negative inotropic, chronotropic, and dromotropic effects on isolated guinea pig atria. In conscious SHR, 30 mg/kg p.o. AHR-16303B completely prevented the vasopressor responses to i.v. 5-HT, and decreased blood pressure (BP) by 24% 3 h after dosing.
 ...
PMID:AHR-16303B, a novel antagonist of 5-HT2 receptors and voltage-sensitive calcium channels. 170 55

1. NG108-15 cells undergo morphological differentiation in response to appropriate culture conditions. We have used patch clamp techniques to compare responses mediated by the 5-HT3 receptor in differentiated and undifferentiated NG108-15 cells. 2. In differentiated cells, desensitization of 5-hydroxytryptamine (5-HT) responses was much slower than in undifferentiated cells. Desensitization in differentiated cells was also highly variable, with half-times varying by greater than 40-fold. Rapidly desensitized responses in differentiated cells were qualitatively similar to the responses of undifferentiated cells. 3. In outside-out patches from undifferentiated cells, single channel currents could be seen after 5-HT application. These channels had a conductance of 12 pS. The 5-HT-activated channels in differentiated cells were too small to observe at the single-channel level. Noise analysis indicated that the channel conductance was approximately 4 pS. In differentiated cells, both rapidly and slowly desensitized responses were generated by channels with essentially the same conductance. 4. The 5-HT responses of differentiated cells were also distinguished from those of undifferentiated cells on the basis of the voltage dependence of desensitization and the curvature of the current-voltage curve. 5. NG108-15 cells can produce different receptor subtypes, which may be expressed in different tissues or at different stages of development. These variations in receptor behavior suggest that there are at least two distinct mechanisms for regulation of the 5-HT3 receptor.
 ...
PMID:Differentiation of NG108-15 cells alters channel conductance and desensitization kinetics of the 5-HT3 receptor. 171 Nov 5

5-HT3 receptors may be present on primary afferent neurons containing substance P (SP), neurokinin A (NKA) or calcitonin gene-related peptide (CGRP). We investigated the release of SP-, NKA- and CGRP-immunoreactivities (IR) from rat spinal cord slices. Thirty mM potassium chloride caused an increased outflow of all three peptides, i.e. 140-190% of spontaneous release. This release was slightly enhanced in the presence of 3 x 10(-5) M 5-hydroxytryptamine (5-HT). In contrast, a significant inhibition of potassium-evoked, but not of basal NKA-IR and CGRP-IR release was observed when 10(-7) M BRL 43694 or ICS 205-930, two specific 5-HT3 receptor antagonists, were superfused together with 5-HT. In conclusion, 5-HT may facilitate the evoked release of peptides from central terminals of primary sensory neurons via 5-HT3 receptors.
 ...
PMID:5-HT3 receptor antagonists inhibit sensory neuropeptide release from the rat spinal cord. 171 37

Isolated segments of the guinea-pig small intestine were vascularly perfused and the release of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) into the portal venous effluent determined by high pressure liquid chromatography with electrochemical detection. Release of acetylcholine from isolated superfused intestinal segments was determined as outflow of [3H]radioactivity from preparations preincubated with [3H]choline. Cisplatin (3 microM) increased the outflow of 5-HT and 5-HIAA by about 90%. At 30 and 100 microM cisplatin decreased the outflow of 5-HT and its metabolite by 40%-50%. The stimulatory effect of cisplatin was consistently observed only when the bicarbonate-phosphate buffer of the Tyrode's solution was replaced by HEPES-buffer. The stimulatory effect of cisplatin was abolished in the absence of extracellular calcium or presence of tetrodotoxin (1 microM). The stimulatory effect of cisplatin was also prevented by hexamethonium (100 microM) or scopolamine (100 nM). The 5-HT3 receptor antagonists ondansetron and ICS 205-930 in concentrations as low as 1 pM also abolished the stimulatory effect of cisplatin. The 5-HT3 receptor antagonist MDL 72222 prevented the stimulatory effect of cisplatin only at a concentration of 1 microM. None of the 5-HT3 receptor antagonists alone significantly altered the outflow of 5-HT and 5-HIAA. Cisplatin (3 microM) enhanced the outflow of [3H]radioactivity from intestinal segments and caused longitudinal muscle contractions that were abolished by 100 nM scopolamine. In conclusion, cisplatin, at concentrations which occur during anti-cancer therapy in humans and induce emesis, increases the release of 5-HT from the enterochromaffin cells of the small intestine of the guinea-pig.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Cisplatin increases the release of 5-hydroxytryptamine (5-HT) from the isolated vascularly perfused small intestine of the guinea-pig: involvement of 5-HT3 receptors. 171 32

1. The effect of micromolar concentrations of divalent metal cations on ion current activated by 5-hydroxytryptamine (5-HT) was investigated in NCB-20 neuroblastoma cells by the use of the whole-cell, patch-clamp technique. 2. Ion current activated by 5-HT in these cells was mimicked by 5-HT3 receptor agonists, blocked by nanomolar concentrations of selective 5-HT3 receptor antagonists and reversed polarity at approximately 0 mV. These properties indicate that this current is carried primarily if not exclusively by the nonspecific cation channel activated by the 5-HT3 receptor. 3. The Group IIb metal cations Cd2+ and Zn2+ and the Group Ib cation Cu2+ inhibited 5-HT-activated current with inhibition increasing in a concentration-dependent manner over micromolar concentrations of the ions. The order of potency of the ions for inhibiting 5-HT-activated current was Zn2+ (IC50 = 20 microM) greater than or equal to Cu2+ (IC50 = 25 microM) greater than Cd2+ (IC50 = 75 microM) at -50 mV. The other divalent metal cations tested (Ba2+, Co2+, Mg2+, Mn2+, and Ni2+) produced little or no inhibition of 5-HT-activated current at concentrations up to 200 microM. 4. Inhibition of 5-HT-activated current by Cd2+ and Zn2+ was dependent on membrane potential with the Kd increasing e-fold per 72 and 52 mV, respectively. Inhibition by Cu2+ was much less voltage dependent with the Kd increasing e-fold per 233 mV. 5. Inhibition by all three cations decreased with increasing concentration of agonist over a range of 5-HT concentrations from 1 to 10 microM.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Inhibition of 5-HT3 receptor-mediated ion current by divalent metal cations in NCB-20 neuroblastoma cells. 172 46


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>